The objective of the present study was to investigate the effectiveness and safety of ultrasound- guided microwave ablation in the treatment of benign thyroid nodules. A total of 474 benign thyroid nodules in 435 patients who underwent ultrasound-guided microwave ablation from September 2012 to August 2015 were included. Nodule volume and thyroid function were measured before treatment and at 1, 3, 6, and 12 months and subsequently after every 6 months. The nodule volume reduction rate and changes of thyroid function were evaluated. The volume of all thyroid nodules significantly decreased after ultrasound-guided microwave ablation. The average volume was 13.07 perpendicular to 0.95ml before treatment, and 1.14 perpendicular to 0.26ml at 12-months follow-up. Themean volume reduction rate was 90% and the final volume reduction rate was 94%. The volume reduction rate of mainly cystic nodules was significantly higher than that of simple solid and mainly solid nodules (all P < 0.05). The pretreatment volume of nodules was positively correlated with the final volume reduction rate at final followup (P = 0.004). No serious complications were observed after treatment. In conclusion, ultrasound-guided microwave ablation is an effective and safe technique for treatment of benign thyroid nodules, and has the potential for clinical applications.